A big, fat picture of body fats

UW Oncology professor Caroline Alexander had a good problem to tackle: She was studying a strain of mice that are resistant to up to 80 percent of tumors. Naturally, she wanted to learn why.

“But none of the resistance mechanisms we were proposing were panning out,” Alexander, a researcher with the UW Carbone Cancer Center and McArdle Laboratory for Cancer Research, says.

The fact that the animals were so resistant to so many different types of cancer – a trait that mimics the health benefits of caloric restriction – led her to think the cause may be related to the animals’ overall metabolism.

“Then I went to a talk from James Ntambi in the UW Biochemistry department, and he had done this remarkable experiment where he knocked out one gene that controls obesity, but only in skin, and found that was enough to keep mice thin,” says Alexander. “That really redirected my attention to skin.”

Alexander went on to find that the mice she studied were highly deficient in a layer of fat associated with skin, called dermal white adipose tissue (dWAT). dWAT plays a crucial role in infection defense, temperature regulation and hair growth. It also appears to be very dynamic, growing thicker or thinner more rapidly than other fat layers.

Images of three different fat layers as whole tissue and as cells shows that fat layers are physically very distinguishable from each other

All fat is not the same: three different fat layers from mice as seen as whole tissue and as cells under the microscope. Source: Daniel Berry et al in Development

Alexander wanted to further study dWAT biology and she was particularly interested in whether this layer is important to human health. However, the standard diagnostic techniques required that mice be euthanized, which not only precluded human study, it also meant changes in fat over time could not be measured in the same animal. While she could have used MRI to safely measure fat in living animals or humans, standard MRI would only allow her to measure total fat content. It would not allow her to distinguish between different types of fat layers.

“All fat is not the same, and you need to look at each depot differently,” says Alexander.

So Alexander and colleagues, including UW Radiology’s Scott Reeder and Diego Hernando, took a different imaging approach. They used a standard MRI machine to collect data, but then computed it differently to distinguish the different fat layers and measure them relative to each other. For this study, they validated their MRI findings with a laborious histological approach.

Different layers of fat in mice in a study

Normal-weight mice grow different fat layers at different rates as they develop diet-induced obesity. These are false-colored MRI images of three fat layers from the same mouse over a 5 week period.

This new technique allowed the researchers to monitor the same mouse over the course of an experiment. For example, they first imaged normal-weight mice, then fed them a high-fat, high-calorie diet and measured changes in different fat layers as they developed obesity. They next imaged human calf regions and found that, at normal body mass index (BMI) values, the thickness of this skin-associated fat layer was variable. Measurements in people with BMIs in the obese range correlated with a thicker fat layer.

Alexander and her colleagues recently published their findings in the journal JCI Insight.

The skin-associated fat layer in human calf regions in order of increasing BMI.

The skin-associated fat layer in human calf regions in order of increasing BMI. Because of this study, different fat layers in humans can be visually distinguished.

Alexander is the first to admit that researchers are far from fully understanding the role this recently-identified fat layer plays in overall human health. For one thing, humans have a skin-associated fat layer that appears to be similar to dWAT, but it is not as clearly demarcated in humans as it in mice. She and colleagues will need to first ensure it is a dWAT equivalent before analogies can be made between mice and men.

“Also, we want to know how to control this layer, so we’re working on that genetically and pharmaceutically,” Alexander says. “Can we compare animals that have thin dWAT with animals that have thick dWAT to find out what is different? Do they resist tumors more? Are they less susceptible to diabetes? That’s what we’re trying to do now.”